This application describes a prospective, randomized phase III clinical trial designed to study adjuvant biologic therapy, using biomarkers, for patients with stage III/IV head and neck cancer. Adjuvant therapy in advanced head and neck cancer after definitive local therapy has not been established, although the survival rate is low because of the high incidence of recurrence and second primary tumor development. The study will use either a combination of 13-cis-retinoic acid (13cRA), alpha- tocopherol, and alpha interferon (IFN-a) to prevent both recurrence and second primary tumors or no treatment. Biomarker studies are incorporated to enhance the understanding of pathobiology for tumor development and biological risk assessment of treatment failure. The hypotheses underlying this application are: (1) head and neck cancer develops in the carcinogen-exposed field (i.e., upper aerodigestive tract) in a multistep process where genomic instability is ongoing, which may lead to development of primary tumors, second primary tumors, or both; (2) adjuvant therapy using 13cRA, alpha-tocopherol, and IFN-a will effectively prevent disease recurrence and second primary tumor development; and (3) biomarkers will define the molecular and cellular changes associated with field cancerization and multistep carcinogenesis and identify individuals at increased risk for recurrence and second primary tumors. With these working hypotheses, the following specific aims are proposed: (1) to determine the efficacy and toxicity of adjuvant therapy with 13cRA, alpha-tocopherol, and IFN-a in preventing recurrence and second primary tumor development in patients with stage III/IV head and neck squamous cell carcinoma following definitive local therapy; (2) to evaluate the overall and disease free survival rates; (3) to evaluate biomarker alterations (p53 alterations, chromosomal changes, retinoic acid receptors [RAR-P] changes, expression of interferon inducible genes, and the interferon signal transduction pathway) in adjacent premalignant lesions and tumor tissue at baseline, at 12 months of treatment and at the time of either recurrence or second primary tumor development; (4) to determine whether biomarker alterations are related to the clinical outcome after adjuvant therapy. To achieve these goals, 180 patients will be randomly assigned to receive 13cRA, alpha-tocopherol, and IFN-a or no treatment for 12 months. For the biomarker studies, p53 expression/mutations by immunohistochemistry and direct sequencing analysis, retinoic acid receptors by RNA in situ hybridization, and interferon responsiveness by interferon receptor analysis, 2',5' oligoadenylate synthetase, and Stat 1 analysis assay will be performed. This translational research of integration of biomarker studies into the adjuvant clinical trial will not only benefit the patients but also promote a unique opportunity to improve pathobiologic understanding of tumorigenesis, risk assessment, and of the biologic basis of therapeutic outcome to the proposed therapy.